title: Inhibition of pre-B cell colony-enhancing factor (PBEF/NAMPT/visfatin) decreases the ability of human neutrophils to generate reactive oxidants but does not impair bacterial killing.
abstract: NAMPT, also known as PBEF and visfatin, can act extracellularly as a cytokine-like molecule or intracellularly as a NAMPT, regulating NAD biosynthesis in the NAD salvage pathway. Inhibitors of NAMPT have anti-inflammatory and anticancer activity and are finding use as therapeutic agents. In view of the importance of NAD metabolism in neutrophil function, we determined the effects of NAMPT inhibition on a variety of neutrophil functions associated with their role in host protection against infections. Incubation of human neutrophils with the NAMPT inhibitor APO866 decreased neutrophil NAD(P)/H levels in a dose- and time-dependent manner but without a concomitant change in cell viability. NAMPT inhibition did not affect the expression of a number of cell-surface receptors involved in adhesion and opsono-phagocytosis, but the respiratory burst was decreased significantly. Whereas opsono-phagocytosis of Staphylococcus aureus was unaffected by NAMPT inhibition, intraphagosomal oxidant production was decreased. However, the killing efficiency of neutrophils was unaffected. These data indicate that therapeutic NAMPT inhibition is unlikely to have deleterious effects on host protection against infections, in spite of this ability to down-regulate neutrophil respiratory burst activity significantly.
authors.affiliation: 1.Biosciences Bldg., Crown St., Liverpool L69 7ZB, UK. s.w.edwards@liv.ac.uk.
authors.forename: Kate J
authors.initials: KJ
authors.lastname: Roberts
authors.forename: Andrew
authors.initials: A
authors.lastname: Cross
authors.forename: Olga
authors.initials: O
authors.lastname: Vasieva
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Moots
authors.forename: Steven W
authors.initials: SW
authors.lastname: Edwards
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001770:Blood Bactericidal Activity; D015550:Cell Degranulation; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D009249:NADP / Q000032:analysis; D009504:Neutrophils / Q000276:immunology / Q000502:physiology*; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors / Q000502:physiology*; D010587:Phagocytosis; D010880:Piperidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016897:Respiratory Burst; D013211:Staphylococcus aureus / Q000276:immunology
chemical_list: D000178:Acrylamides; D016207:Cytokines; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D017382:Reactive Oxygen Species; D009249:NADP; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human
keywords: NAD(P)/H; immune complex; rheumatoid arthritis